The terminal nerve is an anterior cranial nerve that extends between the nasal cavity and hypothalamic/ preoptic area in all classes of jawed vertebrates, including humans. The function of the terminal nerve is poorly understood, but recent research indicates that this peptide-rich nerve serves a neuromodulatory function. The research described in this proposal will elucidate the neuromodulatory effects of terminal nerve-derived peptides on olfactory receptor neurons. The current project has four Specific Aims: (1) to identify and sequence NPY-superfamily and/or FMRFamide-like peptides present in the terminal nerve; (2) to localize terminal nerve cells and fibers containing NPY-superfamily and/or FMRFamide-like peptides relative to those containing another peptide, gonadotropin releasing hormone (GnRH); (3) to characterize the effects of terminal nerve-derived peptides on electrophysiological properties and odorant responses from olfactory receptor neurons; and (4) to investigate the relationships among modulatory effects produced by different terminal nerve-derived peptides. A combination of molecular, biochemical, anatomical, and electrophysiological techniques will be used. This research will contribute to two interrelated goals. The primary goal is to understand the nature of peripheral processing of odorant information. People suffer from olfactory system dysfunction from a variety of causes, including metabolic disorders, hormonal imbalance, and exposure to toxic chemicals. Medications can also alter olfactory system function. Some of the olfactory aberrations associated with these factors may be due to interference with neuromodulatory mechanisms. The secondary goal is to contribute to a general understanding of the physiological function and mechanisms of action of neuropeptide Y (NPY) and other members of this superfamily of peptides. Although NPY is the most prevalent peptide in the brains of mammals, including humans, the actions of this peptide at a cellular and system level are virtually unexplored. NPY has been implicated in the control of feeding and anorexia, as well as seizures, memory disorders, anxiety and depression, and heart problems. In the research proposed here, olfactory receptor neurons will be used as a model system for studying the function and mechanisms of action of NPY.